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1
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Zhang X, Jin M, Chu Y, Liu F, Qu H, Chen C. PRMT6 promotes colorectal cancer progress via activating MYC signaling. J Transl Med 2025; 23:74. [PMID: 39819457 PMCID: PMC11736931 DOI: 10.1186/s12967-025-06097-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 01/08/2025] [Indexed: 01/30/2025] Open
Abstract
Colorectal cancer (CRC) remains a major global health challenge, with high rates of incidence and mortality. This study investigates the role of protein arginine methyltransferase 6 (PRMT6) as an oncogene in CRC and its mechanistic involvement in tumor progression. We found that PRMT6 is significantly overexpressed in CRC tissues compared to adjacent normal tissues and is associated with poorer patient survival. Functional assays demonstrated that PRMT6 promotes CRC cell proliferation, migration, and invasion. Mechanistically, PRMT6 enhances MYC signaling by stabilizing c-MYC through mono-methylation at arginine 371, which inhibits c-MYC poly-ubiquitination and subsequent degradation. This post-translational modification is crucial for PRMT6-induced cancer cell proliferation. Xenograft models further validated that PRMT6 knockdown results in reduced tumor growth and decreased c-MYC levels. Our findings highlight PRMT6 as a key regulator of c-MYC stability and CRC progression, suggesting that targeting PRMT6 or its effects on c-MYC could offer a promising strategy for CRC treatment.
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Affiliation(s)
- Xin Zhang
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wenhua Road, JiNan, 250012, China
| | - Mingxin Jin
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wenhua Road, JiNan, 250012, China
| | - Yali Chu
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wenhua Road, JiNan, 250012, China
| | - Fengjun Liu
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wenhua Road, JiNan, 250012, China
| | - Hui Qu
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wenhua Road, JiNan, 250012, China
| | - Cheng Chen
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wenhua Road, JiNan, 250012, China.
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2
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Cao MT, Feng Y, Zheng YG. Protein arginine methyltransferase 6 is a novel substrate of protein arginine methyltransferase 1. World J Biol Chem 2023; 14:84-98. [PMID: 37901302 PMCID: PMC10600687 DOI: 10.4331/wjbc.v14.i5.84] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/08/2023] [Accepted: 09/26/2023] [Indexed: 10/13/2023] Open
Abstract
BACKGROUND Post-translational modifications play key roles in various biological processes. Protein arginine methyltransferases (PRMTs) transfer the methyl group to specific arginine residues. Both PRMT1 and PRMT6 have emerges as crucial factors in the development and progression of multiple cancer types. We posit that PRMT1 and PRMT6 might interplay directly or in-directly in multiple ways accounting for shared disease phenotypes. AIM To investigate the mechanism of the interaction between PRMT1 and PRMT6. METHODS Gel electrophoresis autoradiography was performed to test the methyltranferase activity of PRMTs and characterize the kinetics parameters of PRMTs. Liquid chromatography-tandem mass spectrometryanalysis was performed to detect the PRMT6 methylation sites. RESULTS In this study we investigated the interaction between PRMT1 and PRMT6, and PRMT6 was shown to be a novel substrate of PRMT1. We identified specific arginine residues of PRMT6 that are methylated by PRMT1, with R106 being the major methylation site. Combined biochemical and cellular data showed that PRMT1 downregulates the enzymatic activity of PRMT6 in histone H3 methylation. CONCLUSION PRMT6 is methylated by PRMT1 and R106 is a major methylation site induced by PRMT1. PRMT1 methylation suppresses the activity of PRMT6.
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Affiliation(s)
- Meng-Tong Cao
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, United States
| | - You Feng
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, United States
| | - Y George Zheng
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, United States
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3
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Chen Q, Hu Q, Chen Y, Shen N, Zhang N, Li A, Li L, Li J. PRMT6 methylation of STAT3 regulates tumor metastasis in breast cancer. Cell Death Dis 2023; 14:655. [PMID: 37813837 PMCID: PMC10562413 DOI: 10.1038/s41419-023-06148-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 09/06/2023] [Accepted: 09/12/2023] [Indexed: 10/11/2023]
Abstract
Overcoming distant metastasis stands as a paramount challenge in enhancing the outcomes of breast cancer treatments. Thus, delving deeper into comprehending the intricate mechanisms underlying breast cancer metastasis becomes imperative, offering potential avenues for pioneering therapeutic approaches. PRMT6, an arginine N-methyltransferase, possesses the ability to methylate both histone and non-histone proteins. It has been reported that methylation of non-histone proteins impacts their cellular localization, stability, and activation, consequently influencing tumor progression. However, the extent to which PRMT6-mediated non-histone protein methylation influences cancer cell metastasis, particularly in the context of breast cancer, remains elusive. In this study, we established that PRMT6 exerted a positive regulatory influence on breast cancer metastasis through both in vivo and in vitro experiments. Mechanistically, we innovatively revealed that PRMT6 asymmetrically di-methylated STAT3 at arginine 729 (STAT3 R729me2a). This modification proved indispensable for STAT3's membrane localization, its interaction with JAK2, STAT3 Y705 phosphorylation, and PRMT6-driven cancer cell metastasis. From a clinical perspective, we unearthed the promising potential of STAT3 R729me2a as a robust prognostic marker for predicting the overall survival time of breast cancer patients. In terms of therapeutic intervention, we demonstrated the significant capability of the PRMT6 inhibitor, EPZ020411, to curtail breast cancer metastasis both in vivo and in vitro. In sum, our study unveils the pivotal biological role of PRMT6-mediated STAT3 R729me2a in breast cancer metastasis and underscores the prospective utility of PRMT6 inhibitors as effective therapeutic strategies against STAT3-driven metastatic breast cancer.
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Affiliation(s)
- Qianzhi Chen
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qingyi Hu
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yan Chen
- Department of Hematology, Wuhan No. 1 Hospital, 430022, Wuhan, China
- Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Na Shen
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ning Zhang
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Anshu Li
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Lei Li
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Junjun Li
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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4
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Trink J, Ahmed U, O'Neil K, Li R, Gao B, Krepinsky JC. Cell surface GRP78 regulates TGFβ1-mediated profibrotic responses via TSP1 in diabetic kidney disease. Front Pharmacol 2023; 14:1098321. [PMID: 36909183 PMCID: PMC9998550 DOI: 10.3389/fphar.2023.1098321] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 02/16/2023] [Indexed: 03/14/2023] Open
Abstract
Introduction: Diabetic kidney disease (DKD) is the leading cause of kidney failure in North America, characterized by glomerular accumulation of extracellular matrix (ECM) proteins. High glucose (HG) induction of glomerular mesangial cell (MC) profibrotic responses plays a central role in its pathogenesis. We previously showed that the endoplasmic reticulum resident GRP78 translocates to the cell surface in response to HG, where it mediates Akt activation and downstream profibrotic responses in MC. Transforming growth factor β1 (TGFβ1) is recognized as a central mediator of HG-induced profibrotic responses, but whether its activation is regulated by cell surface GRP78 (csGRP78) is unknown. TGFβ1 is stored in the ECM in a latent form, requiring release for biological activity. The matrix glycoprotein thrombospondin 1 (TSP1), known to be increased in DKD and by HG in MC, is an important factor in TGFβ1 activation. Here we determined whether csGRP78 regulates TSP1 expression and thereby TGFβ1 activation by HG. Methods: Primary mouse MC were used. TSP1 and TGFβ1 were assessed using standard molecular biology techniques. Inhibitors of csGRP78 were: 1) vaspin, 2) the C-terminal targeting antibody C38, 3) siRNA downregulation of its transport co-chaperone MTJ-1 to prevent GRP78 translocation to the cell surface, and 4) prevention of csGRP78 activation by its ligand, active α2-macroglobulin (α2M*), with the neutralizing antibody Fα2M or an inhibitory peptide. Results: TSP1 transcript and promoter activity were increased by HG, as were cellular and ECM TSP1, and these required PI3K/Akt activity. Inhibition of csGRP78 prevented HG-induced TSP1 upregulation and deposition into the ECM. The HG-induced increase in active TGFβ1 in the medium was also inhibited, which was associated with reduced intracellular Smad3 activation and signaling. Overexpression of csGRP78 increased TSP-1, and this was further augmented in HG. Discussion: These data support an important role for csGRP78 in regulating HG-induced TSP1 transcriptional induction via PI3K/Akt signaling. Functionally, this enables TGFβ1 activation in response to HG, with consequent increase in ECM proteins. Means of inhibiting csGRP78 signaling represent a novel approach to preventing fibrosis in DKD.
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Affiliation(s)
- Jackie Trink
- Division of Nephrology, McMaster University, Hamilton, ON, Canada
| | - Usman Ahmed
- Division of Nephrology, McMaster University, Hamilton, ON, Canada
| | - Kian O'Neil
- Division of Nephrology, McMaster University, Hamilton, ON, Canada
| | - Renzhong Li
- Division of Nephrology, McMaster University, Hamilton, ON, Canada
| | - Bo Gao
- Division of Nephrology, McMaster University, Hamilton, ON, Canada
| | - Joan C Krepinsky
- Division of Nephrology, McMaster University, Hamilton, ON, Canada
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5
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Qin J, Xu J. Arginine methylation in the epithelial-to-mesenchymal transition. FEBS J 2022; 289:7292-7303. [PMID: 34358413 PMCID: PMC10181118 DOI: 10.1111/febs.16152] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 07/23/2021] [Accepted: 08/04/2021] [Indexed: 01/13/2023]
Abstract
Epithelial cells acquire mesenchymal characteristics during embryonic development, wound healing, fibrosis, and in cancer in a processed termed epithelial-to-mesenchymal transition (EMT). Regulatory networks of EMT are controlled by post-transcriptional, translational, and post-translational mechanisms, in which arginine methylation is critically involved. Here, we review arginine methylation-dependent mechanisms that regulate EMT in the aspects of signaling, transcriptional, and splicing regulation.
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Affiliation(s)
- Jian Qin
- Central laboratory, Renmin Hospital of Wuhan University, China
| | - Jian Xu
- Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA.,Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, USA.,Norris Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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6
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Chen Z, Gan J, Wei Z, Zhang M, Du Y, Xu C, Zhao H. The Emerging Role of PRMT6 in Cancer. Front Oncol 2022; 12:841381. [PMID: 35311114 PMCID: PMC8931394 DOI: 10.3389/fonc.2022.841381] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 02/09/2022] [Indexed: 01/01/2023] Open
Abstract
Protein arginine methyltransferase 6 (PRMT6) is a type I PRMT that is involved in epigenetic regulation of gene expression through methylating histone or non-histone proteins, and other processes such as alternative splicing, DNA repair, cell proliferation and senescence, and cell signaling. In addition, PRMT6 also plays different roles in various cancers via influencing cell growth, migration, invasion, apoptosis, and drug resistant, which make PRMT6 an anti-tumor therapeutic target for a variety of cancers. As a result, many PRMT6 inhibitors are being utilized to explore their efficacy as potential drugs for various cancers. In this review, we summarize the current knowledge on the function and structure of PRMT6. At the same time, we highlight the role of PRMT6 in different cancers, including the differentiation of its promotive or inhibitory effects and the underlying mechanisms. Apart from the above, current research progress and the potential mechanisms of PRMT6 behind them were also summarized.
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Affiliation(s)
- Zhixian Chen
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, China
| | - Jianfeng Gan
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, China
| | - Zhi Wei
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, China
| | - Mo Zhang
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, China
| | - Yan Du
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, China
| | - Congjian Xu
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, China
- *Correspondence: Hongbo Zhao, ; Congjian Xu,
| | - Hongbo Zhao
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, China
- *Correspondence: Hongbo Zhao, ; Congjian Xu,
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7
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Structure, Activity and Function of the Protein Arginine Methyltransferase 6. Life (Basel) 2021; 11:life11090951. [PMID: 34575100 PMCID: PMC8470942 DOI: 10.3390/life11090951] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/07/2021] [Accepted: 09/08/2021] [Indexed: 12/25/2022] Open
Abstract
Members of the protein arginine methyltransferase (PRMT) family methylate the arginine residue(s) of several proteins and regulate a broad spectrum of cellular functions. Protein arginine methyltransferase 6 (PRMT6) is a type I PRMT that asymmetrically dimethylates the arginine residues of numerous substrate proteins. PRMT6 introduces asymmetric dimethylation modification in the histone 3 at arginine 2 (H3R2me2a) and facilitates epigenetic regulation of global gene expression. In addition to histones, PRMT6 methylates a wide range of cellular proteins and regulates their functions. Here, we discuss (i) the biochemical aspects of enzyme kinetics, (ii) the structural features of PRMT6 and (iii) the diverse functional outcomes of PRMT6 mediated arginine methylation. Finally, we highlight how dysregulation of PRMT6 is implicated in various types of cancers and response to viral infections.
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8
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Protein arginine methylation: from enigmatic functions to therapeutic targeting. Nat Rev Drug Discov 2021; 20:509-530. [PMID: 33742187 DOI: 10.1038/s41573-021-00159-8] [Citation(s) in RCA: 248] [Impact Index Per Article: 62.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/02/2021] [Indexed: 02/06/2023]
Abstract
Protein arginine methyltransferases (PRMTs) are emerging as attractive therapeutic targets. PRMTs regulate transcription, splicing, RNA biology, the DNA damage response and cell metabolism; these fundamental processes are altered in many diseases. Mechanistically understanding how these enzymes fuel and sustain cancer cells, especially in specific metabolic contexts or in the presence of certain mutations, has provided the rationale for targeting them in oncology. Ongoing inhibitor development, facilitated by structural biology, has generated tool compounds for the majority of PRMTs and enabled clinical programmes for the most advanced oncology targets, PRMT1 and PRMT5. In-depth mechanistic investigations using genetic and chemical tools continue to delineate the roles of PRMTs in regulating immune cells and cancer cells, and cardiovascular and neuronal function, and determine which pathways involving PRMTs could be synergistically targeted in combination therapies for cancer. This research is enhancing our knowledge of the complex functions of arginine methylation, will guide future clinical development and could identify new clinical indications.
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9
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Parbin S, Damodharan S, Rajyaguru PI. Arginine methylation and cytoplasmic mRNA fate: An exciting new partnership. Yeast 2021; 38:441-452. [PMID: 34048611 DOI: 10.1002/yea.3653] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 05/12/2021] [Accepted: 05/20/2021] [Indexed: 12/22/2022] Open
Abstract
Posttranslational modifications play a crucial role in regulating gene expression. Among these modifications, arginine methylation has recently attracted tremendous attention due to its role in multiple cellular functions. This review discusses the recent advances that have established arginine methylation as a major player in determining cytoplasmic messenger RNA (mRNA) fate. We specifically focus on research that implicates arginine methylation in regulating mRNA translation, decay, and RNA granule dynamics. Based on this research, we highlight a few emerging future avenues that will lead to exciting discoveries in this field.
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Affiliation(s)
- Sabnam Parbin
- Department of Biochemistry, Indian Institute of Science, Bangalore, India.,Integrative Genomics Core Unit, University Medical Centre, Göttingen, Göttingen, Germany
| | - Subha Damodharan
- Department of Biochemistry, Indian Institute of Science, Bangalore, India
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10
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Gong S, Maegawa S, Yang Y, Gopalakrishnan V, Zheng G, Cheng D. Licochalcone A is a Natural Selective Inhibitor of Arginine Methyltransferase 6. Biochem J 2020; 478:BCJ20200411. [PMID: 33245113 PMCID: PMC7850898 DOI: 10.1042/bcj20200411] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 11/16/2020] [Accepted: 11/27/2020] [Indexed: 12/12/2022]
Abstract
Arginine methylation is a post-translational modification that is implicated in multiple biological functions including transcriptional regulation. The expression of protein arginine methyltransferases (PRMT) has been shown to be upregulated in various cancers. PRMTs have emerged as attractive targets for the development of new cancer therapies. Here, we describe the identification of a natural compound, licochalcone A, as a novel, reversible and selective inhibitor of PRMT6. Since expression of PRMT6 is upregulated in human breast cancers and is associated with oncogenesis, we used the human breast cancer cell line system to study the effect of licochalcone A treatment on PRMT6 activity, cell viability, cell cycle, and apoptosis. We demonstrated that licochalcone A is a non-S-adenosyl L-methionine (SAM) binding site competitive inhibitor of PRMT6. In MCF-7 cells, it inhibited PRMT6-dependent methylation of histone H3 at arginine 2 (H3R2), which resulted in a significant repression of estrogen receptor activity. Licochalcone A exhibited cytotoxicity towards human MCF-7 breast cancer cells, but not MCF-10A human breast epithelial cells, by upregulating p53 expression and blocking cell cycle progression at G2/M, followed by apoptosis. Thus, licochalcone A has potential for further development as a therapeutic agent against breast cancer.
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Affiliation(s)
- Shuai Gong
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, China
| | - Shinji Maegawa
- Departments of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, U.S.A
| | - Yanwen Yang
- Departments of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, U.S.A
| | - Vidya Gopalakrishnan
- Departments of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, U.S.A
- Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, U.S.A
| | - Guangrong Zheng
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, U.S.A
| | - Donghang Cheng
- Departments of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, U.S.A
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11
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Szulik MW, Davis K, Bakhtina A, Azarcon P, Bia R, Horiuchi E, Franklin S. Transcriptional regulation by methyltransferases and their role in the heart: highlighting novel emerging functionality. Am J Physiol Heart Circ Physiol 2020; 319:H847-H865. [PMID: 32822544 DOI: 10.1152/ajpheart.00382.2020] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Methyltransferases are a superfamily of enzymes that transfer methyl groups to proteins, nucleic acids, and small molecules. Traditionally, these enzymes have been shown to carry out a specific modification (mono-, di-, or trimethylation) on a single, or limited number of, amino acid(s). The largest subgroup of this family, protein methyltransferases, target arginine and lysine side chains of histone molecules to regulate gene expression. Although there is a large number of functional studies that have been performed on individual methyltransferases describing their methylation targets and effects on biological processes, no analyses exist describing the spatial distribution across tissues or their differential expression in the diseased heart. For this review, we performed tissue profiling in protein databases of 199 confirmed or putative methyltransferases to demonstrate the unique tissue-specific expression of these individual proteins. In addition, we examined transcript data sets from human heart failure patients and murine models of heart disease to identify 40 methyltransferases in humans and 15 in mice, which are differentially regulated in the heart, although many have never been functionally interrogated. Lastly, we focused our analysis on the largest subgroup, that of protein methyltransferases, and present a newly emerging phenomenon in which 16 of these enzymes have been shown to play dual roles in regulating transcription by maintaining the ability to both activate and repress transcription through methyltransferase-dependent or -independent mechanisms. Overall, this review highlights a novel paradigm shift in our understanding of the function of histone methyltransferases and correlates their expression in heart disease.
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Affiliation(s)
- Marta W Szulik
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah
| | - Kathryn Davis
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah
| | - Anna Bakhtina
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah
| | - Presley Azarcon
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah
| | - Ryan Bia
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah
| | - Emilee Horiuchi
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah
| | - Sarah Franklin
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah.,Division of Cardiovascular Medicine, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
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12
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Raveendran VV, Al-Haffar K, Kunhi M, Belhaj K, Al-Habeeb W, Al-Buraiki J, Eyjolsson A, Poizat C. Protein arginine methyltransferase 6 mediates cardiac hypertrophy by differential regulation of histone H3 arginine methylation. Heliyon 2020; 6:e03864. [PMID: 32420474 PMCID: PMC7218648 DOI: 10.1016/j.heliyon.2020.e03864] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 04/02/2020] [Accepted: 04/22/2020] [Indexed: 12/11/2022] Open
Abstract
Heart failure remains a major cause of hospitalization and death worldwide. Heart failure can be caused by abnormalities in the epigenome resulting from dysregulation of histone-modifying enzymes. While chromatin enzymes catalyzing lysine acetylation and methylation of histones have been the topic of many investigations, the role of arginine methyltransferases has been overlooked. In an effort to understand regulatory mechanisms implicated in cardiac hypertrophy and heart failure, we assessed the expression of protein arginine methyltransferases (PRMTs) in the left ventricle of failing human hearts and control hearts. Our results show a significant up-regulation of protein arginine methyltransferase 6 (PRMT6) in failing human hearts compared to control hearts, which also occurs in the early phase of cardiac hypertrophy in mouse hearts subjected to pressure overload hypertrophy induced by trans-aortic constriction (TAC), and in neonatal rat ventricular myocytes (NRVM) stimulated with the hypertrophic agonist phenylephrine (PE). These changes are associated with a significant increase in arginine 2 asymmetric methylation of histone H3 (H3R2Me2a) and reduced lysine 4 tri-methylation of H3 (H3K4Me3) observed both in NRVM and in vivo. Importantly, forced expression of PRMT6 in NRVM enhances the expression of the hypertrophic marker, atrial natriuretic peptide (ANP). Conversely, specific silencing of PRMT6 reduces ANP protein expression and cell size, indicating that PRMT6 is critical for the PE-mediated hypertrophic response. Silencing of PRMT6 reduces H3R2Me2a, a mark normally associated with transcriptional repression. Furthermore, evaluation of cardiac contractility and global ion channel activity in live NRVM shows a striking reduction of spontaneous beating rates and prolongation of extra-cellular field potentials in cells expressing low-level PRMT6. Altogether, our results indicate that PRMT6 is a critical regulator of cardiac hypertrophy, implicating H3R2Me2a as an important histone modification. This study identifies PRMT6 as a new epigenetic regulator and suggests a new point of control in chromatin to inhibit pathological cardiac remodeling.
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Affiliation(s)
- Vineesh Vimala Raveendran
- Cardiovascular Research Program, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Kamar Al-Haffar
- Cardiovascular Research Program, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Muhammed Kunhi
- Cardiovascular Research Program, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Karim Belhaj
- College of Medicine, Al Faisal University, PO Box 50927, Riyadh 11211, Saudi Arabia
| | | | | | - Atli Eyjolsson
- Heart Centre, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Coralie Poizat
- Cardiovascular Research Program, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,Masonic Medical Research Institute, Utica, NY 13501, USA
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13
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Morettin A, Bourassa J, Mahadevan K, Trinkle-Mulcahy L, Cote J. Using affinity purification coupled with stable isotope labeling by amino acids in cell culture quantitative mass spectrometry to identify novel interactors/substrates of protein arginine methyltransferases. Methods 2020; 175:44-52. [PMID: 31794835 DOI: 10.1016/j.ymeth.2019.11.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 11/26/2019] [Accepted: 11/26/2019] [Indexed: 12/25/2022] Open
Abstract
The protein arginine methyltransferase family (PRMT) is known as being the catalytic driving force for arginine methylation. This specific type of post translational modification is extensively used in biological processes, and therefore is highly relevant in the pathology of a profusion of diseases. Since altered PRMT expression or deregulation has been shown to contribute to a vast range of those diseases including cancer, their study is of great interest. Although an increasing number of substrates are being discovered for each PRMT, large scale proteomic methods can be used to identify novel interactors/substrates, further elucidating the role that PRMTs perform in physiological or disease states. Here, we describe the use of affinity purification (AP) coupled with stable isotope labeling with amino acids in cell culture (SILAC) quantitative mass spectrometry (MS) to identify protein interactors and substrates of PRMTs. We also explore the possibility of exploiting the fact most PRMTs display lower dissociation rates with their hypomethylated substrates as a strategy to increase the proportion of substrates identified in AP/MS studies.
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Affiliation(s)
- Alan Morettin
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Julie Bourassa
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Kohila Mahadevan
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Laura Trinkle-Mulcahy
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Jocelyn Cote
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
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14
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Chan LH, Zhou L, Ng KY, Wong TL, Lee TK, Sharma R, Loong JH, Ching YP, Yuan YF, Xie D, Lo CM, Man K, Artegiani B, Clevers H, Yan HH, Leung SY, Richard S, Guan XY, Huen MSY, Ma S. PRMT6 Regulates RAS/RAF Binding and MEK/ERK-Mediated Cancer Stemness Activities in Hepatocellular Carcinoma through CRAF Methylation. Cell Rep 2019; 25:690-701.e8. [PMID: 30332648 DOI: 10.1016/j.celrep.2018.09.053] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 07/26/2018] [Accepted: 09/16/2018] [Indexed: 11/18/2022] Open
Abstract
Arginine methylation is a post-translational modification that plays pivotal roles in signal transduction and gene transcription during cell fate determination. We found protein methyltransferase 6 (PRMT6) to be frequently downregulated in hepatocellular carcinoma (HCC) and its expression to negatively correlate with aggressive cancer features in HCC patients. Silencing of PRMT6 promoted the tumor-initiating, metastasis, and therapy resistance potential of HCC cell lines and patient-derived organoids. Consistently, loss of PRMT6 expression aggravated liver tumorigenesis in a chemical-induced HCC PRMT6 knockout (PRMT6-/-) mouse model. Integrated transcriptome and protein-protein interaction studies revealed an enrichment of genes implicated in RAS signaling and showed that PRMT6 interacted with CRAF on arginine 100, which decreased its RAS binding potential and altered its downstream MEK/ERK signaling. Our work describes a critical repressive function for PRMT6 in maintenance of HCC cells by regulating RAS binding and MEK/ERK signaling via methylation of CRAF on arginine 100.
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MESH Headings
- Animals
- Apoptosis
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Proliferation
- DNA Methylation
- Gene Expression Regulation, Neoplastic
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- MAP Kinase Kinase 1/genetics
- MAP Kinase Kinase 1/metabolism
- MAP Kinase Signaling System
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Inbred NOD
- Mice, Knockout
- Mice, Nude
- Mice, SCID
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism
- Protein-Arginine N-Methyltransferases/genetics
- Protein-Arginine N-Methyltransferases/metabolism
- Protein-Arginine N-Methyltransferases/physiology
- TNF Receptor-Associated Factor 3/genetics
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
- raf Kinases/genetics
- raf Kinases/metabolism
- ras Proteins/genetics
- ras Proteins/metabolism
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Affiliation(s)
- Lok Hei Chan
- School of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong, China
| | - Lei Zhou
- School of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong, China
| | - Kai Yu Ng
- School of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong, China
| | - Tin Lok Wong
- School of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong, China
| | - Terence K Lee
- Department of Applied Biology & Chemical Technology, Hong Kong Polytechnic University, Hong Kong, China
| | - Rakesh Sharma
- Proteomics & Metabolomics Core Facility, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China
| | - Jane H Loong
- School of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong, China
| | - Yick Pang Ching
- School of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong, China; State Key Laboratory for Liver Research, University of Hong Kong, Pokfulam, Hong Kong, China
| | - Yun-Fei Yuan
- State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Centre, Guangzhou, China
| | - Dan Xie
- State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Centre, Guangzhou, China
| | - Chung Mau Lo
- State Key Laboratory for Liver Research, University of Hong Kong, Pokfulam, Hong Kong, China; Department of Surgery, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Kwan Man
- State Key Laboratory for Liver Research, University of Hong Kong, Pokfulam, Hong Kong, China; Department of Surgery, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Benedetta Artegiani
- Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Utrecht, the Netherlands
| | - Hans Clevers
- Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Utrecht, the Netherlands
| | - Helen H Yan
- Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Suet Yi Leung
- Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Stéphane Richard
- Lady Davis Institute, Jewish General Hospital, and Departments of Oncology and Medicine, McGill University, Montreal, QC, Canada
| | - Xin-Yuan Guan
- State Key Laboratory for Liver Research, University of Hong Kong, Pokfulam, Hong Kong, China; Department of Clinical Oncology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Michael S Y Huen
- School of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong, China
| | - Stephanie Ma
- School of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong, China; State Key Laboratory for Liver Research, University of Hong Kong, Pokfulam, Hong Kong, China.
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15
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Bouchard C, Sahu P, Meixner M, Nötzold RR, Rust MB, Kremmer E, Feederle R, Hart-Smith G, Finkernagel F, Bartkuhn M, Savai Pullamsetti S, Nist A, Stiewe T, Philipsen S, Bauer UM. Genomic Location of PRMT6-Dependent H3R2 Methylation Is Linked to the Transcriptional Outcome of Associated Genes. Cell Rep 2019; 24:3339-3352. [PMID: 30232013 DOI: 10.1016/j.celrep.2018.08.052] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 07/19/2018] [Accepted: 08/17/2018] [Indexed: 11/20/2022] Open
Abstract
Protein arginine methyltransferase 6 (PRMT6) catalyzes asymmetric dimethylation of histone H3 at arginine 2 (H3R2me2a). This mark has been reported to associate with silent genes. Here, we use a cell model of neural differentiation, which upon PRMT6 knockout exhibits proliferation and differentiation defects. Strikingly, we detect PRMT6-dependent H3R2me2a at active genes, both at promoter and enhancer sites. Loss of H3R2me2a from promoter sites leads to enhanced KMT2A binding and H3K4me3 deposition together with increased target gene transcription, supporting a repressive nature of H3R2me2a. At enhancers, H3R2me2a peaks co-localize with the active enhancer marks H3K4me1 and H3K27ac. Here, loss of H3R2me2a results in reduced KMT2D binding and H3K4me1/H3K27ac deposition together with decreased transcription of associated genes, indicating that H3R2me2a also exerts activation functions. Our work suggests that PRMT6 via H3R2me2a interferes with the deposition of adjacent histone marks and modulates the activity of important differentiation-associated genes by opposing transcriptional effects.
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Affiliation(s)
- Caroline Bouchard
- Institute for Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Hans-Meerwein-Strasse 2, BMFZ, 35043 Marburg, Germany
| | - Peeyush Sahu
- Institute for Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Hans-Meerwein-Strasse 2, BMFZ, 35043 Marburg, Germany
| | - Marion Meixner
- Institute for Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Hans-Meerwein-Strasse 2, BMFZ, 35043 Marburg, Germany
| | - René Reiner Nötzold
- Institute for Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Hans-Meerwein-Strasse 2, BMFZ, 35043 Marburg, Germany
| | - Marco B Rust
- Molecular Neurobiology Group, Institute of Physiological Chemistry, Philipps-University Marburg, Karl-von-Frisch-Strasse 1, 35043 Marburg, Germany
| | - Elisabeth Kremmer
- Institute of Molecular Immunology, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 81377 Munich, Germany
| | - Regina Feederle
- Monoclonal Antibody Core Facility, Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany
| | - Gene Hart-Smith
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia
| | - Florian Finkernagel
- Center for Tumor Biology and Immunology (ZTI), Philipps-University Marburg, Hans-Meerwein-Strasse 3, 35043 Marburg, Germany
| | - Marek Bartkuhn
- Institute for Genetics, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 58-62, 35392 Giessen, Germany
| | - Soni Savai Pullamsetti
- Department of Lung Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Bad Nauheim, Germany
| | - Andrea Nist
- Genomics Core Facility, Philipps-University Marburg, Hans-Meerwein-Strasse 3, 35043 Marburg, Germany
| | - Thorsten Stiewe
- Genomics Core Facility, Philipps-University Marburg, Hans-Meerwein-Strasse 3, 35043 Marburg, Germany; Institute of Molecular Oncology, Philipps-University Marburg, Hans-Meerwein-Strasse 3, 35043 Marburg, Germany
| | - Sjaak Philipsen
- Department of Cell Biology, Erasmus MC, Rotterdam, the Netherlands
| | - Uta-Maria Bauer
- Institute for Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Hans-Meerwein-Strasse 2, BMFZ, 35043 Marburg, Germany.
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16
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Jiang Y, Liu L, Yang S, Cao Y, Song X, Xiao J, Feng H. Black carp PRMT6 inhibits TBK1-IRF3/7 signaling during the antiviral innate immune activation. FISH & SHELLFISH IMMUNOLOGY 2019; 93:108-115. [PMID: 31326582 DOI: 10.1016/j.fsi.2019.07.044] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 07/12/2019] [Accepted: 07/17/2019] [Indexed: 06/10/2023]
Abstract
Protein arginine methylation is a prevalent posttranslational modification and protein arginine methyltransferases 6 (PRMT6) has been identified as a suppressor of TBK1/IRF3 in human and mammals. To explore the role of PRMT6 in teleost fish, PRMT6 homologue of black carp (Mylopharyngodon piceus) has been cloned and characterized in this study. Black carp PRMT6 (bcPRMT6) transcription in host cells varies in response to different stimuli and bcPRMT6 migrates around 43 kDa in the immunoblot assay. Like its mammalian counterpart, bcPRMT6 has been identified to distribute majorly in the nucleus through the immunofluorescent staining assay. bcPRMT6 shows little interferon (IFN) promoter-inducing activity in the reporter assay and bcPRMT6 shows no antiviral activity against either grass carp reovirus (GCRV) or spring viremia of carp virus (SVCV) in plaque assay. When co-expressed with bcPRMT6, the IFN promoter-inducing abilities of black carp TBK1 (bcTBK1) and IRF3/7 (bcIRF3/7) are fiercely attenuated. Accordingly, bcTBK1-mediated antiviral activity in EPC cells is obviously dampened by bcPRMT6. The interaction between bcPRMT6 and bcIRF3/7 has been identified by co-immunoprecipitation assay; however, no direct association between bcPRMT6 and bcTBK1 has been detected. Taken together, our data elucidates for the first time in teleost fish that PRMT6 suppresses TBK1-IRF3/7 signaling during host antiviral innate immune activation.
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Affiliation(s)
- Yuanyuan Jiang
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Science, Hunan Normal University, Changsha, 410081, China
| | - Liqun Liu
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Shisi Yang
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Science, Hunan Normal University, Changsha, 410081, China
| | - Yingyi Cao
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Science, Hunan Normal University, Changsha, 410081, China
| | - Xuejiao Song
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Science, Hunan Normal University, Changsha, 410081, China
| | - Jun Xiao
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Science, Hunan Normal University, Changsha, 410081, China
| | - Hao Feng
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Science, Hunan Normal University, Changsha, 410081, China.
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17
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Rakow S, Pullamsetti SS, Bauer UM, Bouchard C. Assaying epigenome functions of PRMTs and their substrates. Methods 2019; 175:53-65. [PMID: 31542509 DOI: 10.1016/j.ymeth.2019.09.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 09/09/2019] [Accepted: 09/16/2019] [Indexed: 12/20/2022] Open
Abstract
Among the widespread and increasing number of identified post-translational modifications (PTMs), arginine methylation is catalyzed by the protein arginine methyltransferases (PRMTs) and regulates fundamental processes in cells, such as gene regulation, RNA processing, translation, and signal transduction. As epigenetic regulators, PRMTs play key roles in pluripotency, differentiation, proliferation, survival, and apoptosis, which are essential biological programs leading to development, adult homeostasis but also pathological conditions including cancer. A full understanding of the molecular mechanisms that underlie PRMT-mediated gene regulation requires the genome wide mapping of each player, i.e., PRMTs, their substrates and epigenetic marks, methyl-marks readers as well as interaction partners, in a thorough and unambiguous manner. However, despite the tremendous advances in high throughput sequencing technologies and the numerous efforts from the scientific community, the epigenomic profiling of PRMTs as well as their histone and non-histone substrates still remains a big challenge owing to obvious limitations in tools and methodologies. This review will summarize the present knowledge about the genome wide mapping of PRMTs and their substrates as well as the technical approaches currently in use. The limitations and pitfalls of the technical tools along with conventional approaches will be then discussed in detail. Finally, potential new strategies for chromatin profiling of PRMTs and histone substrates will be proposed and described.
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Affiliation(s)
- Sinja Rakow
- Institute for Molecular Biology and Tumor Research (IMT), Philipps University of Marburg, Hans-Meerwein-Str. 2, BMFZ, 35043 Marburg, Germany
| | - Soni Savai Pullamsetti
- Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Bad Nauheim, Germany
| | - Uta-Maria Bauer
- Institute for Molecular Biology and Tumor Research (IMT), Philipps University of Marburg, Hans-Meerwein-Str. 2, BMFZ, 35043 Marburg, Germany
| | - Caroline Bouchard
- Institute for Molecular Biology and Tumor Research (IMT), Philipps University of Marburg, Hans-Meerwein-Str. 2, BMFZ, 35043 Marburg, Germany.
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18
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Okuno K, Akiyama Y, Shimada S, Nakagawa M, Tanioka T, Inokuchi M, Yamaoka S, Kojima K, Tanaka S. Asymmetric dimethylation at histone H3 arginine 2 by PRMT6 in gastric cancer progression. Carcinogenesis 2019; 40:15-26. [PMID: 30508037 DOI: 10.1093/carcin/bgy147] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 09/21/2018] [Accepted: 10/19/2018] [Indexed: 12/13/2022] Open
Abstract
Histone modification plays important molecular roles in development and progression of cancers. Dysregulation of histone H3 arginine (R) methylation is still unknown in primary cancer, including gastric cancer (GC). Although PRMT6 contributes to asymmetric dimethylation at H3R2 (H3R2me2as) in cancer cells, its molecular functions are poorly understood in GC. In this study, we assessed H3R2me2as and PRMT6 expression levels in 133 primary GC tissues by immunohistochemistry. Increased H3R2me2as was found in 68 GC (51.1%) cases and independently related to poor prognosis. PRMT6 was overexpressed in 70 GC (52.6%) and strongly correlated with the global H3R2me2as levels (P < 0.001). By analyzing biological functions of PRMT6 in GC cell lines by lentivirus-based systems, PRMT6 overexpression enhanced global H3R2me2as and invasiveness in vitro, while PRMT6 knockout (PRMT6-KO) suppressed these effects and tumorigenicity in vivo. ChIP and microarray assays demonstrated that PRMT6-KO GC cells decreased the enrichments of H3R2me2as at the promoter regions of PCDH7, SCD and IGFBP5, resulting in upregulation of their gene expression. PRMT6 was recruited to the promoter regions of PCDH7 and SCD in the PRMT6-overexpressed cells. Knockdown of tumor suppressor PCDH7 in the PRMT6-KO GC cells elevated cell migration and invasion. PRMT6 expression inversely correlated with PCDH7 expression in primary GC (P = 0.021). Collectively, our findings strongly indicate that H3R2me2as is a strong prognostic indicator of GC patients, and PRMT6-overexpressing GC cells may acquire invasiveness through direct transcriptional inhibition of PCDH7 by increasing H3R2me2as level. Thus, inhibition of the PRMT6-H3R2me2as pathway could be a promising new therapeutic strategy in GC.
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Affiliation(s)
- Keisuke Okuno
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Gastric Surgery, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Minimally Invasive Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshimitsu Akiyama
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shu Shimada
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masatoshi Nakagawa
- Department of Gastric Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toshiro Tanioka
- Department of Gastric Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mikito Inokuchi
- Department of Gastric Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shoji Yamaoka
- Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazuyuki Kojima
- Department of Gastric Surgery, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Minimally Invasive Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shinji Tanaka
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
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19
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Mouton AJ, Ma Y, Rivera Gonzalez OJ, Daseke MJ, Flynn ER, Freeman TC, Garrett MR, DeLeon-Pennell KY, Lindsey ML. Fibroblast polarization over the myocardial infarction time continuum shifts roles from inflammation to angiogenesis. Basic Res Cardiol 2019; 114:6. [PMID: 30635789 PMCID: PMC6329742 DOI: 10.1007/s00395-019-0715-4] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 01/04/2019] [Indexed: 12/11/2022]
Abstract
Cardiac fibroblasts are the major producers of extracellular matrix (ECM) to form infarct scar. We hypothesized that fibroblasts undergo a spectrum of phenotype states over the course of myocardial infarction (MI) from early onset to scar formation. Fibroblasts were isolated from the infarct region of C57BL/6J male mice (3-6 months old, n = 60) at days 0 (no MI control) and 1, 3, or 7 after MI. Whole transcriptome analysis was performed by RNA-sequencing. Of the genes sequenced, 3371 were differentially expressed after MI. Enrichment analysis revealed that MI day 1 fibroblasts displayed pro-inflammatory, leukocyte-recruiting, pro-survival, and anti-migratory phenotype through Tnfrsf9 and CD137 signaling. MI day 3 fibroblasts had a proliferative, pro-fibrotic, and pro-angiogenic profile with elevated Il4ra signaling. MI day 7 fibroblasts showed an anti-angiogenic homeostatic-like myofibroblast profile and with a step-wise increase in Acta2 expression. MI day 7 fibroblasts relied on Pik3r3 signaling to mediate Tgfb1 effects and Fgfr2 to regulate PI3K signaling. In vitro, the day 3 MI fibroblast secretome stimulated angiogenesis, while day 7 MI fibroblast secretome repressed angiogenesis through Thbs1 signaling. Our results reveal novel mechanisms for fibroblasts in expressing pro-inflammatory molecules and regulating angiogenesis following MI.
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Affiliation(s)
- Alan J Mouton
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 North State St, Jackson, MS, 39216-4505, USA
| | - Yonggang Ma
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 North State St, Jackson, MS, 39216-4505, USA
| | - Osvaldo J Rivera Gonzalez
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 North State St, Jackson, MS, 39216-4505, USA
| | - Michael J Daseke
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 North State St, Jackson, MS, 39216-4505, USA
| | - Elizabeth R Flynn
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 North State St, Jackson, MS, 39216-4505, USA
| | - Tom C Freeman
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK
| | - Michael R Garrett
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Kristine Y DeLeon-Pennell
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 North State St, Jackson, MS, 39216-4505, USA
- Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS, 39216, USA
| | - Merry L Lindsey
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 North State St, Jackson, MS, 39216-4505, USA.
- Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS, 39216, USA.
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20
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Zhao X, Zhou D, Liu Y, Li C, Zhao X, Li Y, Li W. Ganoderma lucidum polysaccharide inhibits prostate cancer cell migration via the protein arginine methyltransferase 6 signaling pathway. Mol Med Rep 2017; 17:147-157. [PMID: 29115463 PMCID: PMC5780085 DOI: 10.3892/mmr.2017.7904] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 06/12/2017] [Indexed: 02/07/2023] Open
Abstract
Prostate cancer is one of the most common types of malignant tumor of men worldwide and the incidence and mortality rate is gradually increasing. At present, the molecular mechanisms of growth and migration in human prostate cancer have not been completely elucidated. Studies have demonstrated that Ganoderma lucidum polysaccharides (GLP) can inhibit cancer. Therefore the present study investigated the effect and molecular mechanism of GLP on cell growth and migration of LNCaP human prostate cancer cells. LNCaP cells were transfected with either a protein arginine methyltransferase 6 (PRMT6) overexpression plasmid or PRMT6 small interfering (si)RNA. The cell growth and migration, and the expression of PRMT6 signaling-associated proteins, were investigated following treatment with 5 and 20 µg/ml GLP. The results demonstrated that GLP inhibited cell growth, induced cell cycle arrest, decreased PRMT6, cyclin-dependent kinase 2 (CDK2), focal adhesion kinase (FAK) and steroid receptor coactivator, (SRC) expression, and increased p21 expression in LNCaP cells, as determined by using a Coulter counter, flow cytometry, and reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. Furthermore, GLP significantly inhibited cell migration, as determined by Transwell migration and scratch assays, and altered CDK2, FAK, SRC and p21 expression in LNCaP cells transfected with the PRMT6 overexpression plasmid. By contrast, PRMT6 knockdown by siRNA reduced the effect of GLP on cell migration. These results indicate that GLP was effective in inhibiting cell growth, the cell cycle and cell migration, and the suppressive effect of GLP on cell migration may occur via the PRMT6 signaling pathway. Therefore, it is suggested that GLP may act as a tumor suppressor with applications in the treatment of prostate cancer. The results of the present study provide both the preliminary theoretical and experimental basis for the investigation of GLP as a therapeutic agent.
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Affiliation(s)
- Xiaohui Zhao
- Oncology Department, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China
| | - Dayu Zhou
- Virology Laboratory, Microbiology Department, The Center of Jinzhou Disease Control and Prevention, Jinzhou, Liaoning 121000, P.R. China
| | - Yunen Liu
- Laboratory of Rescue Center of Severe Wound and Trauma PLA, Emergency Medicine Department, General Hospital of Shenyang Military Command, Shenyang, Liaoning 110016, P.R. China
| | - Chun Li
- College of Mathematics and Physics, Bohai University, Jinzhou, Liaoning 121000, P.R. China
| | - Xiaoguang Zhao
- Oncology Department, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China
| | - Ying Li
- Oncology Department, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China
| | - Wei Li
- Oncology Department, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China
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21
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Structural basis of arginine asymmetrical dimethylation by PRMT6. Biochem J 2016; 473:3049-63. [PMID: 27480107 DOI: 10.1042/bcj20160537] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Accepted: 08/01/2016] [Indexed: 12/19/2022]
Abstract
PRMT6 is a type I protein arginine methyltransferase, generating the asymmetric dimethylarginine mark on proteins such as histone H3R2. Asymmetric dimethylation of histone H3R2 by PRMT6 acts as a repressive mark that antagonizes trimethylation of H3 lysine 4 by the MLL histone H3K4 methyltransferase. PRMT6 is overexpressed in several cancer types, including prostate, bladder and lung cancers; therefore, it is of great interest to develop potent and selective inhibitors for PRMT6. Here, we report the synthesis of a potent bisubstrate inhibitor GMS [6'-methyleneamine sinefungin, an analog of sinefungin (SNF)], and the crystal structures of human PRMT6 in complex, respectively, with S-adenosyl-L-homocysteine (SAH) and the bisubstrate inhibitor GMS that shed light on the significantly improved inhibition effect of GMS on methylation activity of PRMT6 compared with SAH and an S-adenosyl-L-methionine competitive methyltransferase inhibitor SNF. In addition, we also crystallized PRMT6 in complex with SAH and a short arginine-containing peptide. Based on the structural information here and available in the PDB database, we proposed a mechanism that can rationalize the distinctive arginine methylation product specificity of different types of arginine methyltransferases and pinpoint the structural determinant of such a specificity.
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22
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Stein C, Nötzold RR, Riedl S, Bouchard C, Bauer UM. The Arginine Methyltransferase PRMT6 Cooperates with Polycomb Proteins in Regulating HOXA Gene Expression. PLoS One 2016; 11:e0148892. [PMID: 26848759 PMCID: PMC4746130 DOI: 10.1371/journal.pone.0148892] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 01/25/2016] [Indexed: 01/13/2023] Open
Abstract
Protein arginine methyltransferase 6 (PRMT6) catalyses asymmetric dimethylation of histone H3 at arginine 2 (H3R2me2a), which has been shown to impede the deposition of histone H3 lysine 4 trimethylation (H3K4me3) by blocking the binding and activity of the MLL1 complex. Importantly, the genomic occurrence of H3R2me2a has been found to coincide with histone H3 lysine 27 trimethylation (H3K27me3), a repressive histone mark generated by the Polycomb repressive complex 2 (PRC2). Therefore, we investigate here a putative crosstalk between PRMT6- and PRC-mediated repression in a cellular model of neuronal differentiation. We show that PRMT6 and subunits of PRC2 as well as PRC1 are bound to the same regulatory regions of rostral HOXA genes and that they control the differentiation-associated activation of these genes. Furthermore, we find that PRMT6 interacts with subunits of PRC1 and PRC2 and that depletion of PRMT6 results in diminished PRC1/PRC2 and H3K27me3 occupancy and in increased H3K4me3 levels at these target genes. Taken together, our data uncover a novel, additional mechanism of how PRMT6 contributes to gene repression by cooperating with Polycomb proteins.
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Affiliation(s)
- Claudia Stein
- Institute for Molecular Biology and Tumor Research (IMT), Philipps-University of Marburg, Marburg, Germany
| | - René Reiner Nötzold
- Institute for Molecular Biology and Tumor Research (IMT), Philipps-University of Marburg, Marburg, Germany
| | - Stefanie Riedl
- Institute for Molecular Biology and Tumor Research (IMT), Philipps-University of Marburg, Marburg, Germany
| | - Caroline Bouchard
- Institute for Molecular Biology and Tumor Research (IMT), Philipps-University of Marburg, Marburg, Germany
| | - Uta-Maria Bauer
- Institute for Molecular Biology and Tumor Research (IMT), Philipps-University of Marburg, Marburg, Germany
- * E-mail:
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23
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QU LISHUAI, JIN FEI, GUO YANMEI, LIU TAOTAO, XUE RUYI, HUANG XIAOWU, XU MIN, CHEN TAOYANG, NI ZHENGPING, SHEN XIZHONG. Nine susceptibility loci for hepatitis B virus-related hepatocellular carcinoma identified by a pilot two-stage genome-wide association study. Oncol Lett 2016; 11:624-632. [PMID: 26870257 PMCID: PMC4727098 DOI: 10.3892/ol.2015.3958] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2014] [Accepted: 10/26/2015] [Indexed: 12/12/2022] Open
Abstract
Previous studies have indicated that complex interactions among viral, environmental and genetic factors lead to hepatocellular carcinoma (HCC). To identify susceptibility alleles for hepatitis B virus (HBV)-related HCC, the present study conducted a pilot two-phase genome-wide association study (GWAS) in 660 Han Chinese individuals. In phase 1, a total of 500,447 single-nucleotide polymorphisms (SNPs) were genotyped in 50 HCC cases and 50 controls using Affymetrix GeneChip 500k Array Set. In phase 2, 1,152 SNPs were selected from phase 1 and genotyped in 282 cases and 278 controls using the Illumina GoldenGate platform. The prior probability of HCC in control subjects was assigned at 0.01, and false-positive report probability (FPRP) was utilized to evaluate the statistical significance. In phase 1, one SNP (rs2212522) showed a significant association with HCC (Pallele=5.23×10-8; ORallele=4.96; 95% CI, 2.72-9.03). In phase 2, among 27 SNPs with unadjusted Pallele<0.05, 9 SNPs were associated with HCC based on FPRP criteria (FPRP <0.20). The strongest statistical evidence for an association signal was with rs2120243 (combined ORallele=1.76; 95% CI, 1.39-2.22; P=2.00×10-6), which maps within the fourth intron of VEPH1. The second strongest statistical evidence for an association was identified for rs1350171 (combined ORallele=1.66; 95% CI, 1.33-2.07; P=6.48×10-6), which maps to the region downstream of the FZD4 gene. The other potential susceptibility genes included PCDH9, PRMT6, LHX1, KIF2B and L3MBTL4. In conclusion, this pilot two-phase GWAS provides the evidence for the existence of common susceptibility loci for HCC. These genes involved various signaling pathways, including those associated with transforming growth factor β, insulin/phosphoinositide 3 kinase, Wnt and epidermal growth factor receptor. These associations must be replicated and validated in larger studies.
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Affiliation(s)
- LI-SHUAI QU
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - FEI JIN
- Department of Gastroenterology, Shanghai Xuhui Central Hospital, Shanghai 200032, P.R. China
| | - YAN-MEI GUO
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - TAO-TAO LIU
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - RU-YI XUE
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - XIAO-WU HUANG
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - MIN XU
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - TAO-YANG CHEN
- Department of Liver Surgery, Qidong Liver Cancer Institute, Qidong, Jiangsu 226200, P.R. China
| | - ZHENG-PING NI
- Department of Liver Surgery, Qidong Liver Cancer Institute, Qidong, Jiangsu 226200, P.R. China
| | - XI-ZHONG SHEN
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
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24
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Luo M, Li Y, Guo H, Lin S, Chen J, Ma Q, Gu Y, Jiang Z, Gui Y. Protein Arginine Methyltransferase 6 Involved in Germ Cell Viability during Spermatogenesis and Down-Regulated by the Androgen Receptor. Int J Mol Sci 2015; 16:29467-81. [PMID: 26690413 PMCID: PMC4691129 DOI: 10.3390/ijms161226186] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Revised: 11/26/2015] [Accepted: 12/02/2015] [Indexed: 02/05/2023] Open
Abstract
Androgens and the androgen receptor (AR) are of great importance to spermatogenesis and male fertility. AR knockout (ARKO) mice display a complete insensitivity to androgens and male infertility; however, the exact molecular mechanism for this effect remains unclear. In this study, we found that the expression levels of Prmt6 mRNA and protein were significantly up-regulated in the testes of ARKO mice compared to wild type (WT) mice. PRMT6 was principally localized to the nucleus of spermatogonia and spermatocytes by immunofluorescence staining. Furthermore, luciferase assay data showed that AR together with testosterone treatment suppressed Prmt6 transcription via binding to the androgen-responsive element (ARE) of the Prmt6 promoter. Moreover, knockdown of Prmt6 suppressed germ cells migration and promoted apoptosis. In addition, both of these cellular activities could not be enhanced by testosterone treatment. Taken together, these data indicate that PRMT6, which was down-regulated by AR and influenced cell migration and apoptosis of germ cells, could play a potentially important role in spermatogenesis.
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Affiliation(s)
- Manling Luo
- Department of Physiology, Shantou University Medical College, Shantou 515041, China.
| | - Yuchi Li
- Department of Physiology, Shantou University Medical College, Shantou 515041, China.
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen 518036, China.
| | - Huan Guo
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen 518036, China.
- Department of Surgery, Guangzhou Medical University, Guangzhou 510182, China.
| | - Shouren Lin
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen 518036, China.
| | - Jianbo Chen
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen 518036, China.
- Department of Surgery, Anhui Medical University, Hefei 230032, China.
| | - Qian Ma
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen 518036, China.
| | - Yanli Gu
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen 518036, China.
| | - Zhimao Jiang
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen 518036, China.
| | - Yaoting Gui
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen 518036, China.
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25
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Baldwin RM, Haghandish N, Daneshmand M, Amin S, Paris G, Falls TJ, Bell JC, Islam S, Côté J. Protein arginine methyltransferase 7 promotes breast cancer cell invasion through the induction of MMP9 expression. Oncotarget 2015; 6:3013-32. [PMID: 25605249 PMCID: PMC4413634 DOI: 10.18632/oncotarget.3072] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 12/18/2014] [Indexed: 12/05/2022] Open
Abstract
Recent evidence points to the protein arginine methyltransferase (PRMT) family of enzymes playing critical roles in cancer. PRMT7 has been identified in several gene expression studies to be associated with increased metastasis and decreased survival in breast cancer patients. However, this has not been extensively studied. Here we report that PRMT7 expression is significantly upregulated in both primary breast tumour tissues and in breast cancer lymph node metastases. We have demonstrated that reducing PRMT7 levels in invasive breast cancer cells using RNA interference significantly decreased cell invasion in vitro and metastasis in vivo. Conversely, overexpression of PRMT7 in non-aggressive MCF7 cells enhanced their invasiveness. Furthermore, we show that PRMT7 induces the expression of matrix metalloproteinase 9 (MMP9), a well-known mediator of breast cancer metastasis. Importantly, we significantly rescued invasion of aggressive breast cancer cells depleted of PRMT7 by the exogenous expression of MMP9. Our results demonstrate that upregulation of PRMT7 in breast cancer may have a significant role in promoting cell invasion through the regulation of MMP9. This identifies PRMT7 as a novel and potentially significant biomarker and therapeutic target for breast cancer.
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Affiliation(s)
- R Mitchell Baldwin
- Department of Cellular and Molecular Medicine, Ottawa, Ontario, Canada.,Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Nasim Haghandish
- Department of Cellular and Molecular Medicine, Ottawa, Ontario, Canada.,Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Manijeh Daneshmand
- Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Shahrier Amin
- Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada.,Department of Pathology, Ottawa Hospital, Ottawa, Ontario, Canada
| | - Geneviève Paris
- Department of Cellular and Molecular Medicine, Ottawa, Ontario, Canada.,Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Theresa J Falls
- Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - John C Bell
- Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
| | - Shahidul Islam
- Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada.,Department of Pathology, Ottawa Hospital, Ottawa, Ontario, Canada
| | - Jocelyn Côté
- Department of Cellular and Molecular Medicine, Ottawa, Ontario, Canada.,Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
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26
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Zhao XX, Zhang YB, Ni PL, Wu ZL, Yan YC, Li YP. Protein Arginine Methyltransferase 6 (Prmt6) Is Essential for Early Zebrafish Development through the Direct Suppression of gadd45αa Stress Sensor Gene. J Biol Chem 2015; 291:402-12. [PMID: 26487724 DOI: 10.1074/jbc.m115.666347] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2015] [Indexed: 01/13/2023] Open
Abstract
Histone lysine methylation is important in early zebrafish development; however, the role of histone arginine methylation in this process remains unclear. H3R2me2a, generated by protein arginine methyltransferase 6 (Prmt6), is a repressive mark. To explore the role of Prmt6 and H3R2me2a during zebrafish embryogenesis, we identified the maternal characteristic of prmt6 and designed two prmt6-specific morpholino-oligos (MOs) to study its importance in early development, application of which led to early epiboly defects and significantly reduced the level of H3R2me2a marks. prmt6 mRNA could rescue the epiboly defects and the H3R2me2a reduction in the prmt6 morphants. Functionally, microarray data demonstrated that growth arrest and DNA damage-inducible, α, a (gadd45αa) was a significantly up-regulated gene in MO-treated embryos, the activity of which was linked to the activation of the p38/JNK pathway and apoptosis. Importantly, gadd45αa MO and p38/JNK inhibitors could partially rescue the defect of prmt6 morphants, the downstream targets of Prmt6, and the apoptosis ratios of the prmt6 morphants. Moreover, the results of ChIP quantitative real time PCR and luciferase reporter assay indicated that gadd45αa is a repressive target of Prmt6. Taken together, these results suggest that maternal Prmt6 is essential to early zebrafish development by directly repressing gadd45αa.
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Affiliation(s)
- Xin-Xi Zhao
- From the State Key Laboratory of Cell Biology, Shanghai Key Laboratory for Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yun-Bin Zhang
- From the State Key Laboratory of Cell Biology, Shanghai Key Laboratory for Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Pei-Li Ni
- From the State Key Laboratory of Cell Biology, Shanghai Key Laboratory for Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Zhi-Li Wu
- From the State Key Laboratory of Cell Biology, Shanghai Key Laboratory for Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yuan-Chang Yan
- From the State Key Laboratory of Cell Biology, Shanghai Key Laboratory for Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yi-Ping Li
- From the State Key Laboratory of Cell Biology, Shanghai Key Laboratory for Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
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27
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Lopez-Dee ZP, Chittur SV, Patel H, Chinikaylo A, Lippert B, Patel B, Lawler J, Gutierrez LS. Thrombospondin-1 in a Murine Model of Colorectal Carcinogenesis. PLoS One 2015; 10:e0139918. [PMID: 26461935 PMCID: PMC4603676 DOI: 10.1371/journal.pone.0139918] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 09/19/2015] [Indexed: 12/12/2022] Open
Abstract
Colorectal Cancer (CRC) is one of the late complications observed in patients suffering from inflammatory bowel diseases (IBD). Carcinogenesis is promoted by persistent chronic inflammation occurring in IBD. Understanding the mechanisms involved is essential in order to ameliorate inflammation and prevent CRC. Thrombospondin 1 (TSP-1) is a multidomain glycoprotein with important roles in angiogenesis. The effects of TSP-1 in colonic tumor formation and growth were analyzed in a model of inflammation-induced carcinogenesis. WT and TSP-1 deficient mice (TSP-1-/-) of the C57BL/6 strain received a single injection of azoxymethane (AOM) and multiple cycles of dextran sodium sulfate (DSS) to induce chronic inflammation-related cancers. Proliferation and angiogenesis were histologically analyzed in tumors. The intestinal transcriptome was also analyzed using a gene microarray approach. When the area containing tumors was compared with the entire colonic area of each mouse, the tumor burden was decreased in AOM/DSS-treated TSP-1-/- versus wild type (WT) mice. However, these lesions displayed more angiogenesis and proliferation rates when compared with the WT tumors. AOM-DSS treatment of TSP-1-/- mice resulted in significant deregulation of genes involved in transcription, canonical Wnt signaling, transport, defense response, regulation of epithelial cell proliferation and metabolism. Microarray analyses of these tumors showed down-regulation of 18 microRNAs in TSP-1-/- tumors. These results contribute new insights on the controversial role of TSP-1 in cancer and offer a better understanding of the genetics and pathogenesis of CRC.
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Affiliation(s)
- Zenaida P. Lopez-Dee
- Department of Biology, Wilkes University, Wilkes Barre, Pennsylvania, United States of America
| | - Sridar V. Chittur
- Center for Functional Genomics, University of Albany, State University of New York, Renssaeler, New York, United States of America
| | - Hiral Patel
- Department of Biology, Wilkes University, Wilkes Barre, Pennsylvania, United States of America
| | - Aleona Chinikaylo
- Department of Biology, Wilkes University, Wilkes Barre, Pennsylvania, United States of America
| | - Brittany Lippert
- Department of Biology, Wilkes University, Wilkes Barre, Pennsylvania, United States of America
| | - Bhumi Patel
- Department of Biology, Wilkes University, Wilkes Barre, Pennsylvania, United States of America
| | - Jack Lawler
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Linda S. Gutierrez
- Department of Biology, Wilkes University, Wilkes Barre, Pennsylvania, United States of America
- * E-mail:
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28
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Gurunathan G, Yu Z, Coulombe Y, Masson JY, Richard S. Arginine methylation of hnRNPUL1 regulates interaction with NBS1 and recruitment to sites of DNA damage. Sci Rep 2015; 5:10475. [PMID: 26020839 PMCID: PMC4447065 DOI: 10.1038/srep10475] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 04/07/2015] [Indexed: 12/23/2022] Open
Abstract
Arginine methylation is a post-translational modification required for the maintenance of genomic integrity. Cells deficient in protein arginine methyltransferase 1 (PRMT1) have DNA damage signaling defects, defective checkpoint activation and extensive genomic instability. Herein we identify the DNA damage protein and RNA binding protein, hnRNPUL1, to be a substrate of PRMT1. We identify the dimethylation of R584, R618, R620, R645, and R656, as well as the monomethylation of R661 R685 and R690 within hnRNPUL1 in U2OS cells by mass spectrometry. Moreover, we define the arginines within the RGG/RG motifs as the site of methylation by PRMT1 both in vitro and in vivo. The arginines 612, 618, 620, 639, 645, 656 and 661 within the human hnRNPUL1 RGG/RG motifs were substituted with lysines to generate hnRNPUL1RK. hnRNPUL1RK was hypomethylated and lacked the ability to interact with PRMT1, unlike wild type hnRNPUL1. Co-immunoprecipitation studies showed that hnRNPUL1RK had impaired ability to associate with the DNA damage protein NBS1. Moreover, hnRNPUL1RK was not recruited to sites of DNA damage, unlike wild type hnRNPUL1, in the presence of transcriptional inhibitors. These findings define a role for arginine methylation during the DNA damage response to regulate protein-protein interactions for the recruitment at sites of damage.
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Affiliation(s)
- Gayathri Gurunathan
- Terry Fox Molecular Oncology Group and Segal Cancer Center, Bloomfield Center for Research on Aging, Lady Davis Institute for Medical Research and Departments of Oncology and Medicine, McGill University, Montréal, Québec, Canada H3T 1E2
| | - Zhenbao Yu
- Terry Fox Molecular Oncology Group and Segal Cancer Center, Bloomfield Center for Research on Aging, Lady Davis Institute for Medical Research and Departments of Oncology and Medicine, McGill University, Montréal, Québec, Canada H3T 1E2
| | - Yan Coulombe
- Genome Stability Laboratory, Laval University Cancer Research Center, Hôtel-Dieu de Québec (CHUQ), Quebec city, Quebec, Canada, G1R 2J6
| | - Jean-Yves Masson
- Genome Stability Laboratory, Laval University Cancer Research Center, Hôtel-Dieu de Québec (CHUQ), Quebec city, Quebec, Canada, G1R 2J6
| | - Stéphane Richard
- Terry Fox Molecular Oncology Group and Segal Cancer Center, Bloomfield Center for Research on Aging, Lady Davis Institute for Medical Research and Departments of Oncology and Medicine, McGill University, Montréal, Québec, Canada H3T 1E2
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29
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Morettin A, Baldwin RM, Cote J. Arginine methyltransferases as novel therapeutic targets for breast cancer. Mutagenesis 2015; 30:177-89. [DOI: 10.1093/mutage/geu039] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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30
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Gayatri S, Bedford MT. Readers of histone methylarginine marks. BIOCHIMICA ET BIOPHYSICA ACTA 2014; 1839:702-10. [PMID: 24583552 PMCID: PMC4099268 DOI: 10.1016/j.bbagrm.2014.02.015] [Citation(s) in RCA: 103] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2013] [Revised: 01/31/2014] [Accepted: 02/14/2014] [Indexed: 11/15/2022]
Abstract
Arginine methylation is a common posttranslational modification (PTM) that alters roughly 0.5% of all arginine residues in the cells. There are three types of arginine methylation: monomethylarginine (MMA), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA). These three PTMs are enriched on RNA-binding proteins and on histones, and also impact signal transduction cascades. To date, over thirty arginine methylation sites have been cataloged on the different core histones. These modifications alter protein structure, impact interactions with DNA, and also generate docking sites for effector molecules. The primary "readers" of methylarginine marks are Tudor domain-containing proteins. The complete family of thirty-six Tudor domain-containing proteins has yet to be fully characterized, but at least ten bind methyllysine motifs and eight bind methylarginine motifs. In this review, we will highlight the biological roles of the Tudor domains that interact with arginine methylated motifs, and also address other types of interactions that are regulated by these particular PTMs. This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function.
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Affiliation(s)
- Sitaram Gayatri
- Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
| | - Mark T Bedford
- Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
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31
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Di Lorenzo A, Yang Y, Macaluso M, Bedford MT. A gain-of-function mouse model identifies PRMT6 as a NF-κB coactivator. Nucleic Acids Res 2014; 42:8297-309. [PMID: 24939901 PMCID: PMC4117762 DOI: 10.1093/nar/gku530] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Protein arginine methyltransferase 6 (PRMT6) is a nuclear enzyme that modifies histone tails. To help elucidate the biological function of PRMT6 in vivo, we generated transgenic mice that ubiquitously express PRMT6 fused to the hormone-binding portion of the estrogen receptor (ER*). The ER*-PRMT6 fusion is unstable and cytoplasmic, but upon systemic treatment with tamoxifen, it becomes stabilized and translocates into the nucleus. As a result, a dramatic increase in the H3R2me2a histone mark is observed. We found that one consequence of induced ER*-PRMT6 activation is increased IL-6 levels. IL-6 expression is regulated by the nuclear factor-kappa B (NF-κB) transcription factor, and PRMT6 functions as a coactivator of this pathway. We show that PRMT6 directly interacts with RelA, and that its overexpression enhances the transcriptional activity of an ectopic NF-κB reporter and endogenously regulates NF-κB target genes. PRMT6 is recruited, by RelA, to selective NF-κB target promoters upon TNF-α stimulation. Moreover, ER*-PRMT6 activation causes RelA accumulation in the nucleus. In summary, we observe that PRMT6 is recruited to chromatin at selective NF-κB target promoters, where it likely impacts the histone code and/or methylates other chromatin-associated proteins to facilitate transcription.
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Affiliation(s)
- Alessandra Di Lorenzo
- The University of Texas MD Anderson Cancer Center, Science Park, P.O. Box 389, Smithville, TX 78957, USA
| | - Yanzhong Yang
- The University of Texas MD Anderson Cancer Center, Science Park, P.O. Box 389, Smithville, TX 78957, USA
| | - Marc Macaluso
- The University of Texas MD Anderson Cancer Center, Science Park, P.O. Box 389, Smithville, TX 78957, USA
| | - Mark T Bedford
- The University of Texas MD Anderson Cancer Center, Science Park, P.O. Box 389, Smithville, TX 78957, USA
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32
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Singhroy DN, Mesplède T, Sabbah A, Quashie PK, Falgueyret JP, Wainberg MA. Automethylation of protein arginine methyltransferase 6 (PRMT6) regulates its stability and its anti-HIV-1 activity. Retrovirology 2013; 10:73. [PMID: 23866860 PMCID: PMC3750301 DOI: 10.1186/1742-4690-10-73] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Accepted: 07/09/2013] [Indexed: 01/10/2023] Open
Abstract
Background Protein arginine methyltransferase 6 (PRMT6) is a nuclear enzyme that methylates arginine residues on histones and transcription factors. In addition, PRMT6 inhibits HIV-1 replication in cell culture by directly methylating and interfering with the functions of several HIV-1 proteins, i.e. Tat, Rev and nucleocapsid (NC). PRMT6 also displays automethylation capacity but the role of this post-translational modification in its antiretroviral activity remains unknown. Results Here we report the identification by liquid chromatography-mass spectrometry of R35 within PRMT6 as the target residue for automethylation and have confirmed this by site-directed mutagenesis and in vitro and in vivo methylation assays. We further show that automethylation at position 35 greatly affects PRMT6 stability and is indispensable for its antiretroviral activity, as demonstrated in HIV-1 single-cycle TZM-bl infectivity assays. Conclusion These results show that PRMT6 automethylation plays a role in the stability of this protein and that this event is indispensible for its anti-HIV-1 activity.
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Affiliation(s)
- Diane N Singhroy
- McGill University AIDS Centre, Lady Davis for Medical Research, Jewish General Hospital, 3755 Cote Sainte Catherine, Montreal, QC, H3T 1E2, Canada
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Sivakumaran H, Lin MH, Apolloni A, Cutillas V, Jin H, Li D, Wei T, Harrich D. Overexpression of PRMT6 does not suppress HIV-1 Tat transactivation in cells naturally lacking PRMT6. Virol J 2013; 10:207. [PMID: 23800116 PMCID: PMC3695826 DOI: 10.1186/1743-422x-10-207] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Accepted: 06/20/2013] [Indexed: 01/09/2023] Open
Abstract
Background Protein arginine methyltransferase 6 (PRMT6) can methylate the HIV-1 Tat, Rev and nucleocapsid proteins in a manner that diminishes each of their functions in in vitro assays, and increases the stability of Tat in human cells. In this study, we explored the relationship between PRMT6 and HIV-1 Tat by determining the domains in each protein required for interaction. Methods Through domain mapping and immunoprecipitation experiments, we determined that both the amino and carboxyl termini of PRMT6, and the activation domain within Tat are essential for interaction. Mutation of the basic domain of Tat did not affect the ability of PRMT6 to interact with Tat. Results We next used the A549 human alveolar adenocarcinoma cell line, which naturally expresses undetectable levels of PRMT6, as a model for testing the effects of PRMT6 on Tat stability, transactivation, and HIV-1 replication. As previously observed, steady state levels and the protein half-life of Tat were increased by the ectopic expression of PRMT6. However, no down regulation of Tat transactivation function was observed, even with over 300-fold molar excess of PRMT6 plasmid. We also observed no negative effect on HIV-1 infectivity when A549 producer cells overexpressed PRMT6. Conclusions We show that PRMT6 requires the activation domain, but surprisingly not the basic domain, of Tat for protein interaction. This interaction between Tat and PRMT6 may impact upon pathogenic effects attributed to Tat during HIV-1 infection other than its function during transactivation.
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Affiliation(s)
- Haran Sivakumaran
- Queensland Institute of Medical Research, Molecular Virology Laboratory, 300 Herston Road, Herston, Brisbane 4006, Australia
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Kim NH, Kim SN, Seo DW, Han JW, Kim YK. PRMT6 overexpression upregulates TSP-1 and downregulates MMPs: Its implication in motility and invasion. Biochem Biophys Res Commun 2013; 432:60-5. [DOI: 10.1016/j.bbrc.2013.01.085] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Accepted: 01/23/2013] [Indexed: 10/27/2022]
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Lo Sardo A, Altamura S, Pegoraro S, Maurizio E, Sgarra R, Manfioletti G. Identification and characterization of new molecular partners for the protein arginine methyltransferase 6 (PRMT6). PLoS One 2013; 8:e53750. [PMID: 23326497 PMCID: PMC3542376 DOI: 10.1371/journal.pone.0053750] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Accepted: 12/03/2012] [Indexed: 12/13/2022] Open
Abstract
PRMT6 is a protein arginine methyltransferase that has been implicated in transcriptional regulation, DNA repair, and human immunodeficiency virus pathogenesis. Only few substrates of this enzyme are known and therefore its cellular role is not well understood. To identify in an unbiased manner substrates and potential regulators of PRMT6 we have used a yeast two-hybrid approach. We identified 36 new putative partners for PRMT6 and we validated the interaction in vivo for 7 of them. In addition, using invitro methylation assay we identified 4 new substrates for PRMT6, extending the involvement of this enzyme to other cellular processes beyond its well-established role in gene expression regulation. Holistic approaches create molecular connections that allow to test functional hypotheses. The assembly of PRMT6 protein network allowed us to formulate functional hypotheses which led to the discovery of new molecular partners for the architectural transcription factor HMGA1a, a known substrate for PRMT6, and to provide evidences for a modulatory role of HMGA1a on the methyltransferase activity of PRMT6.
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Affiliation(s)
| | - Sandro Altamura
- Department of Life Sciences, University of Trieste, Trieste, Italy
| | - Silvia Pegoraro
- Department of Life Sciences, University of Trieste, Trieste, Italy
| | - Elisa Maurizio
- Department of Life Sciences, University of Trieste, Trieste, Italy
| | - Riccardo Sgarra
- Department of Life Sciences, University of Trieste, Trieste, Italy
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Abstract
There are nine protein arginine methyltransferases (PRMTs) encoded in mammalian genomes, the protein products of which catalyse three types of arginine methylation--monomethylation and two types of dimethylation. Protein arginine methylation is an abundant modification that has been implicated in signal transduction, gene transcription, DNA repair and mRNA splicing, among others. Studies have only recently linked this modification to carcinogenesis and metastasis. Sequencing studies have not generally found alterations to the PRMTs; however, overexpression of these enzymes is often associated with various cancers, which might make some of them viable targets for therapeutic strategies.
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Affiliation(s)
- Yanzhong Yang
- Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, 1808 Park Road 1C, P.O. BOX 389, Smithville, Texas 78957, USA
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Protein Arginine Methyltransferases (PRMTs): promising targets for the treatment of pulmonary disorders. Int J Mol Sci 2012. [PMID: 23202904 PMCID: PMC3497278 DOI: 10.3390/ijms131012383] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Protein arginine methylation is a novel posttranslational modification that plays a pivotal role in a variety of intracellular events, such as signal transduction, protein-protein interaction and transcriptional regulation, either by the direct regulation of protein function or by metabolic products originating from protein arginine methylation that influence nitric oxide (NO)-dependent processes. A growing body of evidence suggests that both mechanisms are implicated in cardiovascular and pulmonary diseases. This review will present and discuss recent research on PRMTs and the methylation of non-histone proteins and its consequences for the pathogenesis of various lung disorders, including lung cancer, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease and asthma. This article will also highlight novel directions for possible future investigations to evaluate the functional contribution of arginine methylation in lung homeostasis and disease.
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Phalke S, Mzoughi S, Bezzi M, Jennifer N, Mok WC, Low DHP, Thike AA, Kuznetsov VA, Tan PH, Voorhoeve PM, Guccione E. p53-Independent regulation of p21Waf1/Cip1 expression and senescence by PRMT6. Nucleic Acids Res 2012; 40:9534-42. [PMID: 22987071 PMCID: PMC3479215 DOI: 10.1093/nar/gks858] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
p21 is a potent cyclin-dependent kinase inhibitor that plays a role in promoting G1 cell cycle arrest and cellular senescence. Consistent with this role, p21 is a downstream target of several tumour suppressors and oncogenes, and it is downregulated in the majority of tumours, including breast cancer. Here, we report that protein arginine methyltransferase 6 (PRMT6), a type I PRMT known to act as a transcriptional cofactor, directly represses the p21 promoter. PRMT6 knock-down (KD) results in a p21 derepression in breast cancer cells, which is p53-independent, and leads to cell cycle arrest, cellular senescence and reduced growth in soft agar assays and in severe combined immunodeficiency (SCID) mice for all the cancer lines examined. We finally show that bypassing the p21-mediated arrest rescues PRMT6 KD cells from senescence, and it restores their ability to grow on soft agar. We conclude that PRMT6 acts as an oncogene in breast cancer cells, promoting growth and preventing senescence, making it an attractive target for cancer therapy.
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Affiliation(s)
- Sameer Phalke
- Division of Cancer Genetics and Therapeutics, Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore 138673
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Vilen ST, Suojanen J, Salas F, Risteli J, Ylipalosaari M, Itkonen O, Koistinen H, Baumann M, Stenman UH, Sorsa T, Salo T, Nyberg P. Trypsin-2 enhances carcinoma invasion by processing tight junctions and activating ProMT1-MMP. Cancer Invest 2012; 30:583-92. [PMID: 22909050 DOI: 10.3109/07357907.2012.716467] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Enhanced proteolysis and altered tight junction (TJ) proteins associate with carcinoma invasion. We hypothesized that trypsin-2, a tumor-associated serine proteinase, induces tongue carcinoma invasion by activating pro-membrane type-1 matrix metalloproteinase (MT1-MMP) and disturbing the TJs. The effects of invasion were analyzed using trypsin-2 over-expressing human tongue squamous cell carcinoma cells (Try2-HSC-3) in vitro and in vivo. The invasion of Try2-HSC-3 cells was increased in mouse xenografts and human organotypic model. Trypsin-2 activated proMT1-MMP, as well as altered the expression of TJ protein claudin-7. In conclusion, trypsin-2 over-expression enhanced tongue carcinoma cell invasion by various genetic and proteolytic mechanisms.
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Affiliation(s)
- Suvi-Tuuli Vilen
- Institute of Dentistry, University of Helsinki, and Department of Oral and Maxillofacial Diseases, Helsinki University Hospital, Helsinki, Finland.
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Kleinschmidt MA, de Graaf P, van Teeffelen HAAM, Timmers HTM. Cell cycle regulation by the PRMT6 arginine methyltransferase through repression of cyclin-dependent kinase inhibitors. PLoS One 2012; 7:e41446. [PMID: 22916108 PMCID: PMC3423397 DOI: 10.1371/journal.pone.0041446] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2010] [Accepted: 06/27/2012] [Indexed: 12/02/2022] Open
Abstract
PRMT6 belongs to the family of Protein Arginine Methyltransferase (PRMT) enzymes that catalyze the methylation of guanidino nitrogens of arginine residues. PRMT6 has been shown to modify the tail of histone H3, but the in vivo function of PRMT6 is largely unknown. Here, we show that PRMT6 regulates cell cycle progression. Knockdown of PRMT6 expression in the human osteosarcoma cell line U2OS results in an accumulation of cells at the G2 checkpoint. Loss of PRMT6 coincides with upregulation of p21 and p27, two members of the CIP/KIP family of cyclin-dependent kinase (CDK) inhibitors. Gene expression and promoter analysis show that p21 and p27 are direct targets of PRMT6, which involves methylation of arginine-2 of histone H3. Our findings imply arginine methylation of histones by PRMT6 in cell cycle regulation.
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Affiliation(s)
| | | | | | - H. Th. Marc Timmers
- Department of Molecular Cancer Research and Netherlands Proteomics Center, University Medical Center Utrecht, Utrecht, The Netherlands
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Stein C, Riedl S, Rüthnick D, Nötzold RR, Bauer UM. The arginine methyltransferase PRMT6 regulates cell proliferation and senescence through transcriptional repression of tumor suppressor genes. Nucleic Acids Res 2012; 40:9522-33. [PMID: 22904088 PMCID: PMC3479209 DOI: 10.1093/nar/gks767] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The protein arginine methyltransferase 6 (PRMT6) is a coregulator of gene expression and executes its repressing as well as activating function by asymmetric dimethylation of histone H3 at R2 (H3 R2me2a). Given that elevated expression levels of PRMT6 have been reported in various cancer types, we explore here its role in cell proliferation and senescence. We find that knockdown of PRMT6 results in proliferation defects of transformed as well as non-transformed cells, causes G1-phase arrest and induces senescence. This phenotype is accompanied by transcriptional upregulation of important cell cycle regulators, most prominently the cyclin-dependent kinase (CDK) inhibitor gene p21 (p21CIP1/WAF1, CDKN1A) and p16 (p16INK4A, CDKN2A). Chromatin immuno-precipitation analysis reveals that the p21 gene is a direct target of PRMT6 and the corresponding histone mark H3 R2me2a. Using a cell model of oncogene-induced senescence (OIS), in which p21 is an essential activator of the senescent phenotype, we show that PRMT6 expression declines upon induction of senescence and conversely p21 gene expression increases. Moreover, overexpression of PRMT6 leads to reduced levels of OIS. These findings indicate that the transcriptional repressor activity of PRMT6 facilitates cell proliferation and blocks senescence by regulation of tumor suppressor genes and that this might contribute to the oncogenic capacity of PRMT6.
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Affiliation(s)
- Claudia Stein
- Institute for Molecular Biology and Tumor Research, University of Marburg, Emil-Mannkopff-Strasse 2, 35032 Marburg, Germany
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Neault M, Mallette FA, Vogel G, Michaud-Levesque J, Richard S. Ablation of PRMT6 reveals a role as a negative transcriptional regulator of the p53 tumor suppressor. Nucleic Acids Res 2012; 40:9513-21. [PMID: 22904064 PMCID: PMC3479207 DOI: 10.1093/nar/gks764] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Arginine methylation of histones is a well-known regulator of gene expression. Protein arginine methyltransferase 6 (PRMT6) has been shown to function as a transcriptional repressor by methylating the histone H3 arginine 2 [H3R2(me2a)] repressive mark; however, few targets are known. To define the physiological role of PRMT6 and to identify its targets, we generated PRMT6(-/-) mouse embryo fibroblasts (MEFs). We observed that early passage PRMT6(-/-) MEFs had growth defects and exhibited the hallmarks of cellular senescence. PRMT6(-/-) MEFs displayed high transcriptional levels of p53 and its targets, p21 and PML. Generation of PRMT6(-/-); p53(-/-) MEFs prevented the premature senescence, suggesting that the induction of senescence is p53-dependent. Using chromatin immunoprecipitation assays, we observed an enrichment of PRMT6 and H3R2(me2a) within the upstream region of Trp53. The PRMT6 association and the H3R2(me2a) mark were lost in PRMT6(-/-) MEFs and an increase in the H3K4(me3) activator mark was observed. Our findings define a new regulator of p53 transcriptional regulation and define a role for PRMT6 and arginine methylation in cellular senescence.
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Affiliation(s)
- Mathieu Neault
- Terry Fox Molecular Oncology Group and Bloomfield Center for Research on Aging, Segal Cancer Centre, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Department of Oncology, McGill University, Montréal, Québec, Canada, H3T 1E2
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Abstract
The coordinated recruitment of epigenetic regulators of gene expression by transcription factors such as RUNX1 (AML1, acute myeloid leukemia 1) is crucial for hematopoietic differentiation. Here, we identify protein arginine methyltransferase 6 (PRMT6) as a central functional component of a RUNX1 corepressor complex containing Sin3a and HDAC1 in human hematopoietic progenitor cells. PRMT6 is recruited by RUNX1 and mediates asymmetric histone H3 arginine-2 dimethylation (H3R2me2a) at megakaryocytic genes in progenitor cells. H3R2me2a keeps RUNX1 target genes in an intermediate state with concomitant H3K27me3 and H3K4me2 but not H3K4me3. Upon megakaryocytic differentiation PRMT6 binding is lost, the H3R2me2a mark decreases and a coactivator complex containing WDR5/MLL and p300/pCAF is recruited. This leads to an increase of H3K4me3 and H3K9ac, which result in augmented gene expression. Our results provide novel mechanistic insight into how RUNX1 activity in hematopoietic progenitor cells maintains differentiation genes in a suppressed state but poised for rapid transcriptional activation.
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Wang YC, Li C. Evolutionarily conserved protein arginine methyltransferases in non-mammalian animal systems. FEBS J 2012; 279:932-45. [PMID: 22251447 DOI: 10.1111/j.1742-4658.2012.08490.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Protein arginine methylation is catalyzed by members of the protein arginine methyltransferase (PRMT) family. In the present review, nine PRMTs identified in mammals (human) were used as templates to survey homologous PRMTs in 10 animal species with a completed sequence available in non-mammalian vertebrates, invertebrate chordates, echinoderms, arthropods, nematodes and cnidarians. We show the conservation of the most typical type I PRMT1 and type II PRMT5 in all of the species examined, the wide yet different distribution of PRMT3, 4 and 7 in non-mammalian animals, the vertebrate-restricted distribution of PRMT8 and the special reptile/avian-deficient distribution of PRMT2 and 6. We summarize the basic functions of each PRMT and focus on the current investigations of PRMTs in the non-mammalian animal models, including Xenopus, fish (zebrafish, flounder and medaka), Drosophila and Caenorhabditis elegans. Studies in the model systems not only complement the understanding of the functions of PRMTs in mammals, but also provide valuable information about their evolution, as well as their critical roles and interplays.
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Affiliation(s)
- Yi-Chun Wang
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan
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45
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Obianyo O, Thompson PR. Kinetic mechanism of protein arginine methyltransferase 6 (PRMT6). J Biol Chem 2012; 287:6062-71. [PMID: 22219200 DOI: 10.1074/jbc.m111.333609] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The protein arginine methyltransferases (PRMTs) are a family of enzymes that catalyze the mono- and dimethylation of arginine residues in a variety of proteins. Although these enzymes play important roles in a variety of cellular processes, aberrant PRMT activity is associated with several disease states, including heart disease and cancer. In an effort to guide the development of inhibitors targeting individual PRMTs, we initiated studies to characterize the molecular mechanisms of PRMT catalysis. Herein, we report studies on the kinetic mechanism of PRMT6. Initial velocity, product inhibition, and dead-end analog inhibition studies with the AcH4-21 and R1 peptides, as well as their monomethylated versions, indicate, in contrast to a previous report, that PRMT6 utilizes a rapid equilibrium random mechanism with dead-end EAP and EBQ complexes.
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Affiliation(s)
- Obiamaka Obianyo
- Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, USA
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Henkin J, Volpert OV. Therapies using anti-angiogenic peptide mimetics of thrombospondin-1. Expert Opin Ther Targets 2011; 15:1369-86. [PMID: 22136063 DOI: 10.1517/14728222.2011.640319] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
INTRODUCTION The role of hrombospondin-1 (TSP1) as a major endogenous angiogenesis inhibitor has been confirmed by numerous studies and subsequent mechanistic discoveries. It has yielded a new class of potential drugs against cancer and other angiogenesis-driven diseases. AREAS COVERED An overview of TSP1 functions and molecular mechanisms, including regulation and signaling. Functions in endothelial and non-endothelial cells, with emphasis on the role of TSP1 in the regulation of angiogenesis and inflammation. The utility of duplicating these activities for drug discovery. Past and current literature on endogenous TSP1 and its role in the progression of cancer and non-cancerous pathological conditions is summarized, as well as the research undertaken to identify and optimize short bioactive peptides derived from the two TSP1 anti-angiogenic domains, which bind CD47 and CD36 cell surface receptors. Lastly, there is an overview of the efficacy of some of these peptides in pre-clinical and clinical models of angiogenesis-dependent disease. EXPERT OPINION It is concluded that TSP1-derived peptides and peptide mimetics hold great promise as future agents for the treatment of cancer and other diseases driven by excessive angiogenesis. They may fulfill unmet medical needs including neovascular ocular disease and the diseases of the female reproductive tract including ovarian cancer.
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Affiliation(s)
- Jack Henkin
- Chemistry of Life Processes Institute, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208, USA
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Heaslip AT, Nishi M, Stein B, Hu K. The motility of a human parasite, Toxoplasma gondii, is regulated by a novel lysine methyltransferase. PLoS Pathog 2011; 7:e1002201. [PMID: 21909263 PMCID: PMC3164638 DOI: 10.1371/journal.ppat.1002201] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2010] [Accepted: 06/23/2011] [Indexed: 11/29/2022] Open
Abstract
Protozoa in the phylum Apicomplexa are a large group of obligate intracellular parasites. Toxoplasma gondii and other apicomplexan parasites, such as Plasmodium falciparum, cause diseases by reiterating their lytic cycle, comprising host cell invasion, parasite replication, and parasite egress. The successful completion of the lytic cycle requires that the parasite senses changes in its environment and switches between the non-motile (for intracellular replication) and motile (for invasion and egress) states appropriately. Although the signaling pathway that regulates the motile state switch is critical to the pathogenesis of the diseases caused by these parasites, it is not well understood. Here we report a previously unknown mechanism of regulating the motility activation in Toxoplasma, mediated by a protein lysine methyltransferase, AKMT (for Apical complex lysine (K) methyltransferase). AKMT depletion greatly inhibits activation of motility, compromises parasite invasion and egress, and thus severely impairs the lytic cycle. Interestingly, AKMT redistributes from the apical complex to the parasite body rapidly in the presence of egress-stimulating signals that increase [Ca2+] in the parasite cytoplasm, suggesting that AKMT regulation of parasite motility might be accomplished by the precise temporal control of its localization in response to environmental changes. Toxoplasma gondii is one of the most successful human parasites, infecting ∼20% of the total world population. It is the most common cause of congenital neurological defects in humans, and an agent for devastating opportunistic infections in immunocompromised patients. To cause diseases, Toxoplasma gondii and other related parasites, such as Plasmodium falciparum, must reiterate their lytic cycle, comprising host cell infection, intracellular replication and parasite egress. At each step of the lytic cycle, the parasite tightly regulates its motility, being completely immotile while intracellular, and becoming highly motile as it leaves the host cell. Changes in local ionic conditions are known to trigger this rapid transition from immotile to motile. In this study, we report a previously unknown mechanism of regulating the motility activation in Toxoplasma, mediated by a novel protein lysine methyltransferase, AKMT (for Apical complex lysine (K) methyltransferase). The depletion of this protein greatly inhibits the parasite's ability to invade into and egress from the host cell due to impaired motility activation. Interestingly, the localization of AKMT in the parasite is sensitive to egress-stimulating signals, suggesting that AKMT regulation of parasite motility might be accomplished by the precise temporal control of its localization in response to environmental changes.
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Affiliation(s)
- Aoife T. Heaslip
- Department of Biology, Indiana University, Bloomington, Indiana, United States of America
| | - Manami Nishi
- Department of Biology, Indiana University, Bloomington, Indiana, United States of America
| | - Barry Stein
- Department of Biology, Indiana University, Bloomington, Indiana, United States of America
| | - Ke Hu
- Department of Biology, Indiana University, Bloomington, Indiana, United States of America
- * E-mail:
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Waldmann T, Izzo A, Kamieniarz K, Richter F, Vogler C, Sarg B, Lindner H, Young NL, Mittler G, Garcia BA, Schneider R. Methylation of H2AR29 is a novel repressive PRMT6 target. Epigenetics Chromatin 2011; 4:11. [PMID: 21774791 PMCID: PMC3164600 DOI: 10.1186/1756-8935-4-11] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2011] [Accepted: 07/20/2011] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Covalent histone modifications are central to all DNA-dependent processes. Modifications of histones H3 and H4 are becoming well characterised, but knowledge of how H2A modifications regulate chromatin dynamics and gene expression is still very limited. RESULTS To understand the function of H2A modifications, we performed a systematic analysis of the histone H2A methylation status. We identified and functionally characterised two new methylation sites in H2A: R11 (H2AR11) and R29 (H2AR29). Using an unbiased biochemical approach in combination with candidate assays we showed that protein arginine methyltransferase (PRMT) 1 and PRMT6 are unique in their ability to catalyse these modifications. Importantly we found that H2AR29me2 is specifically enriched at genes repressed by PRMT6, implicating H2AR29me2 in transcriptional repression. CONCLUSIONS Our data establishes R11 and R29 as new arginine methylation sites in H2A. We identified the specific modifying enzymes involved, and uncovered a novel functional role of H2AR29me2 in gene silencing in vivo. Thus this work reveals novel insights into the function of H2A methylation and in the mechanisms of PRMT6-mediated transcriptional repression.
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Affiliation(s)
- Tanja Waldmann
- MPI for Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany
- University of Konstanz, Doerenkamp-Zbinden chair, Universitätsstr. 10, 78457 Konstanz, Germany
| | - Annalisa Izzo
- MPI for Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany
| | - Kinga Kamieniarz
- MPI for Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany
| | - Florian Richter
- MPI for Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany
| | - Christine Vogler
- MPI for Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany
| | - Bettina Sarg
- Innsbruck Medical University, Division of Clinical Biochemistry, Biocenter, Fritz-Pregl-Str. 3, 6020 Innsbruck, Austria
| | - Herbert Lindner
- Innsbruck Medical University, Division of Clinical Biochemistry, Biocenter, Fritz-Pregl-Str. 3, 6020 Innsbruck, Austria
| | - Nicolas L Young
- Princeton University, Department of Molecular Biology, 415 Shultz Laboratory, Princeton, NJ 08540, USA
| | - Gerhard Mittler
- MPI for Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany
| | - Benjamin A Garcia
- Princeton University, Department of Molecular Biology, 415 Shultz Laboratory, Princeton, NJ 08540, USA
| | - Robert Schneider
- MPI for Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany
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Abstract
Post-translational modification of histones provides an important regulatory platform for processes such as gene expression, DNA replication and repair, chromosome condensation and segregation and apoptosis. Disruption of these processes has been linked to the multistep process of carcinogenesis. We review the aberrant covalent histone modifications observed in cancer, and discuss how these epigenetic changes, caused by alterations in histone-modifying enzymes, can contribute to the development of a variety of human cancers. As a conclusion, a new terminology 'histone onco-modifications' is proposed to describe post-translational modifications of histones, which have been linked to cancer. This new term would take into account the active contribution and importance of these histone modifications in the development and progression of cancer.
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Tsai YJ, Pan H, Hung CM, Hou PT, Li YC, Lee YJ, Shen YT, Wu TT, Li C. The predominant protein arginine methyltransferase PRMT1 is critical for zebrafish convergence and extension during gastrulation. FEBS J 2011; 278:905-17. [PMID: 21214862 DOI: 10.1111/j.1742-4658.2011.08006.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Protein arginine methyltransferase (PRMT)1 is the predominant type I methyltransferase in mammals. In the present study, we used zebrafish (Danio rerio) as the model system to elucidate PRMT1 expression and function during embryogenesis. Zebrafish prmt1 transcripts were detected from the zygote period to the early larva stage. Knockdown of prmt1 by antisense morpholino oligo (AMO) resulted in delayed growth, shortened body-length, curled tails and cardiac edema. PRMT1 protein level, type I protein arginine methyltransferase activity, specific asymmetric protein arginine methylation and histone H4 R3 methylation all decreased in the AMO-injected morphants. The morphants showed defective convergence and extension and the abnormalities were more severe at the posterior than the anterior parts. Cell migration defects suggested by the phenotypes were not only observed in the morphant embryos, but also in a cellular prmt1 small-interfering RNA knockdown model. Rescue of the phenotypes by co-injection of wild-type but not catalytic defective prmt1 mRNA confirmed the specificity of the AMO and the requirement of methyltransferase activity in early development. The results obtained in the present study demonstrate a direct link of early development with protein arginine methylation catalyzed by PRMT1.
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Affiliation(s)
- Yun-Jung Tsai
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan
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